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Research & Scholarship

Current Research and Scholarly Interests

My research focuses on the physiolgogic and biomarker characteristics of early acute lung injury (ALI) prior to need for mechanical ventilation. While, to date no pharmacologic treatment has improved survival in ALI, following the paradigm of early goal directed therapy for severe sepsis, clinical benefit may derive from identifying patients and initiating treatment prior to the need for positive pressure ventilation (and therefore prior to meeting current study entry criteria).

This is a Phase 1, open label, dose escalation, multi-center clinical trial of Allogeneic
Bone Marrow-Derived Human Mesenchymal Stem Cells (hMSCs) for the treatment of Acute
Respiratory Distress Syndrome (ARDS). The purpose of this study is to assess the safety of
hMSCs in patients with ARDS.

Abstract

Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index (P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index (P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) (P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index (P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

Abstract

ABSTRACT: Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation.

Abstract

Many critically ill patients are transferred to other care facilities instead of to home at hospital discharge.To identify patient-related factors associated with hospital discharge to a care facility after critical illness and to estimate the magnitude of risk associated with each factor.Retrospective cohort study of 548 survivors of critical illness in a medical intensive care unit. Multivariable logistic regression was used to identify independent risk factors for discharge to a care facility. Only the first 72 hours of intensive care were analyzed.Approximately one-quarter of the survivors of critical illness were discharged to a care facility instead of to home. This event occurred more commonly in older patients, even after adjustment for severity of illness and comorbid conditions (odds ratio [OR] 1.8 for patients ? 65 years of age vs patients < 65 years; 95% confidence interval [CI], 1.1-3.1; P = .02). The risk was greatest for patients who received mechanical ventilation (OR, 3.4; 95% CI, 2.0-5.8; P < .001) or had hospitalizations characterized by severe cognitive dysfunction (OR, 8.1; 95% CI, 1.3-50.6; P = .02) or poor strength and/or mobility (OR, 31.7; 95% CI, 6.4-157.3; P < .001). The model showed good discrimination (area under the curve, 0.82; 95% CI, 0.77-0.86).The model, which did not include baseline function or social variables, provided good discrimination between patients discharged to a care facility after critical illness and patients discharged to home. These results suggest that future research should focus on the debilitating effects of respiratory failure and on conditions with cognitive and neuromuscular sequelae.

Abstract

Despite significant advances in our understanding of the pathophysiology of acute lung injury, a lung-protective strategy of mechanical ventilation remains the only therapy with a proven survival advantage. Numerous pharmacologic therapies have failed to show benefit in multicenter clinical trials. The paradigm of early, goal-directed therapy of sepsis suggests greater clinical benefit may derive from initiating therapy prior to the onset of respiratory failure that requires mechanical ventilation. Thus, there is heightened interest in more accurate and complete characterization of high-risk patient populations and identification of patients in the early stage of acute lung injury, prior to the need for mechanical ventilation. This article discusses the growing literature on clinical predictors of acute lung injury (including risk factors for specific subgroups) with an emphasis on transfusion-related risk factors and recent research targeting the early identification of high-risk patients and those with early acute lung injury prior to the onset of respiratory failure.

Abstract

Over the past 2 decades, measurement of biomarkers in both the airspaces and plasma early in the course of acute lung injury has provided new insights into the mechanisms of lung injury. In addition, biologic markers of cell-specific injury, acute inflammation, and altered coagulation correlate with mortality from acute lung injury in several single center studies as well as in multicenter clinical trials. To date, biomarkers have been measured largely for research purposes. However, with improved understanding of their role in the pathogenesis of acute lung injury, biomarkers may play an important role in early detection of lung injury, risk stratification for clinical trials, and, ultimately, tailoring specific therapies to individual patients. This article provides a review of biologic markers in acute lung injury, with an emphasis on recent analysis of results from multicenter clinical trials.

Abstract

Despite being a focus of intensive investigation, acute lung injury (ALI) remains a major cause of morbidity and mortality. However, the current consensus definition impedes identification of patients with ALI before they require mechanical ventilation. To establish a definition of early ALI (EALI), we carried out a prospective cohort study to identify clinical predictors of progression to ALI.Potential cases of EALI were identified by daily screening of chest radiographs (CXRs) for all adult emergency department and new medicine service admissions at Stanford University Hospital.Of 1,935 screened patients with abnormal CXRs, we enrolled 100 patients admitted with bilateral opacities present < 7 days and not due exclusively to left atrial hypertension. A total of 33 of these 100 patients progressed to ALI requiring mechanical ventilation during their hospitalization. Progression to ALI was associated with immunosuppression, the modified Rapid Emergency Medicine Score, airspace opacities beyond the bases, systemic inflammatory response syndrome, and the initial oxygen requirement (> 2 L/min). On multivariate analysis, only an initial oxygen requirement > 2 L/min predicted progression to ALI (odds ratio, 8.1; 95% confidence interval, 2.7 to 24.5). A clinical diagnosis of EALI, defined by hospital admission with bilateral opacities on CXR not exclusively due to left atrial hypertension and an initial oxygen requirement of > 2 L/min, was 73% sensitive and 79% specific for progression to ALI.A new clinical definition of EALI may have value in identifying patients with ALI early in their disease course.

Abstract

Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

Abstract

Distinguishing pulmonary edema due to acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) from hydrostatic or cardiogenic edema is challenging in critically ill patients. B-type natriuretic peptide (BNP) can effectively identify congestive heart failure in the emergency room setting but, despite increasing use, its diagnostic utility has not been validated in the intensive care unit (ICU).We performed a prospective, blinded cohort study in the medical and surgical ICUs at the University of Chicago Hospitals. Patients were eligible if they were admitted to the ICU with respiratory distress, bilateral pulmonary edema and a central venous catheter suggesting either high-pressure (cardiogenic) or low-pressure (ALI/ARDS) pulmonary edema. BNP levels were measured within 48 hours of ICU admission and development of pulmonary edema and onward up to three consecutive days. All levels were drawn simultaneously with the measurement of right atrial or pulmonary artery wedge pressure. The etiology of pulmonary edema--cardiogenic or ALI/ARDS--was determined by three intensivists blinded to BNP levels.We enrolled a total of 54 patients (33 with ALI/ARDS and 21 with cardiogenic edema). BNP levels were lower in patients with ALI/ARDS than in those with cardiogenic edema (496 +/- 439 versus 747 +/- 476 pg/ml, P = 0.05). At an accepted cutoff of 100 pg/ml, specificity for the diagnosis of ALI/ARDS was high (95.2%) but sensitivity was poor (27.3%). Cutoffs at higher BNP levels improved sensitivity at considerable cost to specificity. Invasive measures of filling pressures correlated poorly with initial BNP levels and subsequent day BNP values fluctuated unpredictably and without correlation with hemodynamic changes and net fluid balance.BNP levels drawn within 48 hours of admission to the ICU do not reliably distinguish ALI/ARDS from cardiogenic edema, do not correlate with invasive hemodynamic measurements, and do not track predictably with changes in volume status on consecutive daily measurements.

Abstract

To determine the prevalence of myocardial ischemia in mechanically ventilated patients with coronary risk factors and compare periods of sedative interruption vs. sedative infusion.Prospective, blinded observational study.Medical intensive care unit of tertiary care medical center.Intubated, mechanically ventilated patients with established coronary artery disease risk factors.Continuous three-lead Holter monitors with ST-segment analysis by a blinded cardiologist were used to detect myocardial ischemia. Ischemia was defined as ST-segment elevation or depression of >0.1 mV from baseline.Comparisons between periods of awakening from sedation vs. sedative infusion were made. Vital signs, catecholamine levels, and time with ischemia detected by Holter monitor during the two periods were compared. Heart rate, mean arterial pressure, rate-pressure product, respiratory rate, and catecholamine levels were all significantly higher during sedative interruption. Eighteen of 74 patients (24%) demonstrated ischemic changes. Patients with myocardial ischemia had a longer intensive care unit length of stay (17.4+/-17.5 vs. 9.6+/-6.7 days, p=.04). Despite changes in vital signs and catecholamine levels during sedative interruption, fraction of ischemic time did not differ between the time awake vs. time sedated [median [interquartile range] of 0% [0, 0] compared with 0% [0, 0] while they were sedated [p=.17]). The finding of similar fractions of ischemic time between awake and sedated states persisted with analysis of the subgroup of 18 patients with ischemia.Myocardial ischemia is common in critically ill mechanically ventilated patients with coronary artery disease risk factors. Daily sedative interruption is not associated with an increased occurrence of myocardial ischemia in these patients.

Abstract

Central venous pressure (CVP) provides important information for the management of critically ill patients. The external jugular vein (EJV) is easier to visualize than the internal jugular vein and may give a reliable estimate of CVP.To determine the usefulness of the EJV examination in detecting abnormal CVP values, we performed a prospective blinded evaluation comparing it with CVP measured using an indwelling catheter in critically ill patients with central venous catheters. Blinded EJV examinations were performed by clinicians with 3 experience levels (attending physicians, residents and fellows, and interns and fourth-year medical students) to estimate CVP (categorized as low [=5 cm of water] or high [>/=10 cm of water]). The usefulness of the EJV examination in discriminating low vs high CVP was measured using receiver operating characteristic curve analysis.One hundred eighteen observations were recorded among 35 patients. The range of CVP values was 2 to 20 cm of water. The EJV was easier to visualize than the internal jugular vein (mean visual analog scale score, 8 vs 5; P

Abstract

The acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967. However, despite considerable efforts, early progress in treatment was slowed by lack of consistent definitions and appropriately powered clinical trials. In 1994, the American-European Consensus Conference on ARDS established criteria defining ARDS as well as acute lung injury (ALI). Additionally, the conference established research directives and international coordination of clinical studies. Current incidence of ALI in the United States is estimated at 200,000 cases per year with a mortality rate approaching 40%. Mechanical ventilation, using positive end-expiratory pressure and reduced tidal volumes and inspiratory pressures, along with improved supportive care has increased survival rates. However, to date, pharmacological therapies have failed to improve survival in multicenter clinical trials. This article focuses on clinical treatments for ALI that have been tested in phase II and III clinical trials as well as a discussion of potential future therapies.